Testing for HIV does not simply end with the diagnosis that the virus is present in a patient; caregivers also need to track the disease’s progress to adjust ongoing treatment. Yet tests for monitoring HIV infection require sophisticated instruments, well-trained clinicians and expensive lab ware. All those are in short supply on HIV’s front line in places such as rural sub-Saharan Africa. “It’s a problem not just of cost,” explains hematologist Helen Lee of the University of Cambridge in the UK. “It’s a problem of having access.” In the last year, stripped-down standalone tests have appeared on the market, offering rural patients a cheaper, faster count of their CD4 immune cells. And in the coming months, a class of tests that measure viral load should enter routine point-of-care use, too, offering caregivers a choice of simple tools for measuring HIV infections.
Almost a decade ago, the US National Institutes of Health kicked off its Molecular Libraries Initiative to provide academic researchers with access to the high-throughput screening tools needed to identify new therapeutic compounds. Europe now seems keen on catching up.
Last month, the Innovative Medicines Initiative (IMI), a €2 billion ($2.6 billion) Brussels-based partnership between the European Commission and the European Federation of Pharmaceutical Industries and Associations (EFPIA), invited proposals to build a molecular screening facility for drug discovery in Europe that will combine the inquisitiveness of academic scientists with industry know-how. The IMI’s call for tenders says the facility will counter “fragmentation” between these sectors.
The IMI will offer €80 million over five years to the consortium selected to build up and manage a centralized screening infrastructure and a library of up to 500,000 compounds. Expressions of interest from qualified academic-industry partnerships are due in mid-May.
Major pharmaceutical companies have more experience with high-throughput screening than do most academic institutes. Yet companies often limit tests of their closely held candidate chemicals to a fraction of potential disease targets. By pooling chemical libraries and screening against a more diverse set of targets—and identifying more molecular interactions—both academics and pharmaceutical companies stand to gain, says Hugh Laverty, an IMI project manager.
The IMI already has commitments from seven members of the EFPIA to contribute 50,000 compounds each, and future academic partners are expected to donate between 100,000 and 200,000 total. (The NIH similarly has around 300,000 chemically diverse compounds in its small-molecule repository.)
Onlookers note the challenge of handling so many molecular candidates. Whoever manages the IMI’s ‘European Screening Centre’ will need to develop an efficient process for preselecting compounds to make the high-throughput screening worth the cost to taxpayers, says Robert Damoiseaux, scientific director of the Molecular Screening Shared Resource (MSSR) at the University of California–Los Angeles. Damoiseaux recommends that Europeans look across the pond for insight on this: “It’s certainly really useful to compare notes with American researchers and have a look at which lessons can be learned, what paradigms worked and what didn’t.”
Ultimately, a facility as large as the proposed European Screening Center should be more efficient than the smaller sites that already exist around Europe, says Gerardo Turcatti, who directs the Biomolecular Screening Facility at the Swiss Federal Institute of Technology in Lausanne. He adds, however, that sorting out intellectual property in any collaboration that also involves industrial applications will be a challenge.
Laverty says the IMI will help the winning consortium negotiate the particulars with the industry partners. “We’re very aware of intellectual property concerns,” he explains, adding that identifying a promising compound might trigger milestone payments to a compound’s contributor.
Regulatory authorities such as the US Food and Drug Administration and European Medicines Agency face continual criticism for their plodding pace of drug approval decisions. In 2009, the last year for which complete data are available, the median time for a standard review of a drug application in the US was 13 months—30% longer than the agency’s target for such reviews. But even with this situation, it’s undeniable that both agencies devote far more human and financial resources to the process than most other countries can afford to spend on their own.
To keep up, many other medical regulatory authorities are banding together with one another to share the expertise and clinical results needed to make faster decisions. On 20 June, for example, New Zealand’s Prime Minister John Key announced that the establishment of the Australia New Zealand Therapeutic Products Agency—stalled for several years—would proceed as planned. And, the month before, as the World Health Organization (WHO) held its annual assembly in Geneva, a concurrent meeting of health ministers from countries in the Gulf Cooperation Council approved pricing standards for drugs in its six member states from across the Arabian Peninsula.
“There is increasing cooperation and work sharing between regulators,” says Lembit Rägo, coordinator of Quality Assurance and Safety for Medicines at the WHO in Geneva and author of an April 2011 report on international harmonization of regulatory efforts (Clin. Pharmacol. Ther. 89, 503–512, 2011).
Delays are often worst in what the WHO calls “less-resourced countries,” because in some cases those countries wait until a trusted authority such as the FDA or EMA has approved a drug before making a decision. The WHO has estimated that 90% of drug regulatory agencies in sub-Saharan Africa faced circumstances that hindered their function and could impede their ability to guarantee the safety of medicines within their borders.
To make the situation even more daunting, many drugs that have potential use in developing countries—such as those for tropical disease—may not be priorities in North America and Europe. As such, they face longer delays between development and reaching their target markets.
What’s more, drug approvals in one part of the world are not always applicable elsewhere, as the case of Sanofi’s Priftin (rifapentine) shows. The FDA approved the French drugmaker’s tuberculosis drug on the basis of clinical trials that excluded HIV-affected individuals, even though these are the people who would constitute 70% of the sub-Saharan African market, according to a recent paper calling for more coordinated review of medicines for neglected disease (PLoS Med. 8, e1000411, 2011). “Streamlining and coordinating regulatory approval could bring new medicines—and better health—to literally millions of patients in the developing world,” says lead study author Mary Moran of Policy Cures, a health-policy analysis firm in Sydney.
Hoping for harmony
When it comes to the matter of regulatory collaboration, the East African Community may be furthest along among regional efforts in Africa. Its harmonization initiative held a startup meeting in 2007 in Geneva to adapt regulatory guidelines from the WHO. Despite holdups, last year its members won a one-year pilot grant from the Bill & Melinda Gates Foundation to launch a program for consolidating the technical requirements makers of new drugs must submit for approval, among other efficiencies. The New Partnership for Africa’s Development, an economic growth program of the African Union, has also been coordinating an initiative within the continent since 2008, with the goal of speeding drug registration.
Countries that would share their drug approval processes face other challenges, such as establishing common standards for laboratory quality control and agreeing on how to review the post-marketing efficacy of a drug. To streamline drug reviews, most wealthy countries are parties to the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), a set of guidelines developed by pharmaceutical makers and government regulators. For even more help, some participate in separate work-sharing agreements, such as Switzerland, Canada, Australia and Singapore, who signed one in 2006.
New Zealand has taken this one step further. In 2008, the country elected to recognize some regulatory decisions from other countries rather than complete full evaluations. At the time, its regulatory agency, the Medicines and Medical Devices Safety Authority (Medsafe), had a backlog of 360 drug applications, including those for both new and generic medicines, and took more than three years to complete an approval on average, according to a presentation by Medsafe group manager Stewart Jessamine at the International Conference of Drug Regulatory Authorities meeting in Singapore last November.
Devoting its resources to the generic drugs that make up most New Zealand applications allowed Medsafe to refer over 60% of new medicines to the abbreviated approval process, which takes fewer than 200 days on average. “The preferred strategic solution, however, is that Medsafe join with the Therapeutic Goods Administration of Australia,” Jessamine says, a merger delayed since 2007 that will now resume.
Pharmaceutical producers welcome a unified regulatory environment. “This is where it’s moving to,” says Paul Herrling, head of the Novartis Institutes for Developing World Medical Research in Basel.
Thirty years ago this month, scientists first reported the existence of AIDS, and in the intervening decades researchers have focused steady efforts on prevention, long-term treatments such as antiretroviral drugs, and patient care. What has fallen in and out of fashion during that time is seeking a ‘cure’ for HIV. That changed when scientists reported that they had cured one man of the virus through a bone marrow transplant (Blood 117, 2791–2799, 2011). But the circumstances of that 2007 transplant were unique, and researchers say they are uncertain about how to fund additional cure-directed research without cannibalizing other components of the global HIV/AIDS research machine.
“That’s the tricky part,” says Bertrand Audoin, executive director of the International AIDS Society (IAS), a Geneva-based HIV research and education association. “Actually, to be honest, I’m glad it’s not for me to decide.”
To address the issue, the IAS has invited a working group to its biennial research meeting in Rome this July to hash out ideas about how to include cure research within the existing framework of HIV/AIDS studies. “Our goal after the Rome meeting is to have enough scientific ideas to reach out to new donors,” Audoin says, though they will only ask for pledges this year. Funding requests for specific avenues of cure research will have to wait until the working group releases a more formal scientific strategy at the July 2012 meeting in Washington, DC.
So far, funding earmarked for cure research is a tiny fraction of overall HIV/AIDS spending, says David Margolis, a virologist at the University of North Carolina at Chapel Hill and a member of the IAS working group. The US National Institutes of Health (NIH) is funding cure-related research to the tune of $13 million a year out of its $3.5 billion annual AIDS research budget, with the Bill & Melinda Gates Foundation and the California Institute for Regenerative Medicine contributing comparable amounts. The Rome meeting should help researchers nail down “several specific areas or projects that should be developed,” Margolis says. The AIDS Policy Project, an advocacy group in Philadelphia, has been lobbying for the NIH to raise its investment in cure research to $240 million a year.
Cure-related research takes various forms. As researchers have grown better at suppressing HIV activity with antiretroviral drugs, they are now reaching for other tools that might draw out the virus from its cellular hiding places in order to destroy it. Margolis and his colleagues, including Daria Hazuda of the drug giant Merck, have patented a therapy using a leukemia drug called Zolinza (vorinostat) because it forces dormant, HIV-hosting immune cells into dividing and exposes the virus to a possible sterilizing cure. “Purging is going to be one approach, but there are going to be others,” says immunologist James Hoxie of the University of Pennsylvania School of Medicine in Philadelphia, including gene therapy that modifies a patient’s immune system with mutant genes that help keep HIV under control, without antiretroviral drugs. “The people who control funding need to take advantage of extraordinary events,” such as the successful gene therapy reported in Blood, Hoxie says. “This should encourage additional funding, not remove it from other programs.”
Deenan Pillay, a virologist at University College London, argues that the idea of clearing HIV in the body head on, which has not been accomplished with any other virus, is “nice to rationalize by saying it’s more cost effective” than lifelong antiretroviral treatment. “But the big issue in HIV is not necessarily eradication versus treatment but rather making the benefits of treatment available worldwide,” he says. Achieving either one will require prioritization. “If we want to do it properly, the best way is not to look at who can give more money,” Audoin says, “but first to agree on what the scientific strategy should be and what we really want to achieve.”